Author: Jalal Saleh Michika, PhD, MACE

LONDON (Reuters) – Ghana, Kenya and Malawi will pilot the world’s first malaria vaccine from 2018, offering it for babies and children in high-risk areas as part of real-life trials, the World Health Organization said on Monday.

The injectable vaccine, called RTS,S or Mosquirix, was developed by British drugmaker GlaxoSmithKline to protect children from the most deadly form of malaria in Africa.

In clinical trials it proved only partially effective, and it needs to be given in a four-dose schedule, but is the first regulator-approved vaccine against the mosquito-borne disease.

The WHO, which is in the process of assessing whether to add the shot to core package of WHO-recommended measures for malaria prevention, has said it first wants to see the results of on-the-ground testing in a pilot programme.

“Information gathered in the pilot will help us make decisions on the wider use of this vaccine,” Matshidiso Moeti, the WHO’s African regional director, said in a statement as the three pilot countries were announced.

“Combined with existing malaria interventions, such a vaccine would have the potential to save tens of thousands of lives in Africa.”

Malaria kills around 430,000 people a year, the vast majority of them babies and young children in sub-Saharan Africa. Global efforts in the last 15 years cut the malaria death toll by 62 percent between 2000 and 2015.

The WHO pilot programme will assess whether the Mosquirix’s protective effect in children aged 5 to 17 months can be replicated in real-life.

It will also assess the feasibility of delivering the four doses needed, and explore the vaccine’s potential role in reducing the number of children killed by the disease.

The WHO said Malawi, Kenya and Ghana were chosen for the pilot due to several factors, including having high rates of malaria as well as good malaria programmes, wide use of bed-nets, and well-functioning immunisation programmes.

Each of the three countries will decide on the districts and regions to be included in the pilots, the WHO said, with high malaria areas getting priority since these are where experts expect to see most benefit from the use of the vaccine.

RTS,S was developed by GSK in partnership with the non-profit PATH Malaria Vaccine Initiative and part-funded by the Bill & Melinda Gates Foundation.

The WHO said in November it had secured full funding for the first phase of the RTS,S pilots, with $15 million from the Global Fund to Fight AIDS, Tuberculosis and up to $27.5 million and $9.6 million respectively from the GAVI Vaccine Alliance and UNITAID for the first four years of the programme.

Malaria parasites cause red blood cells to become bendier, helping the parasites to enter and cause infection, says a new study.

Malaria is caused by a family of parasites that are carried by mosquitoes. Once parasites enter the body through a mosquito bite, they multiply in the liver before invading red blood cells where they cause the symptoms of malaria disease.

This could also mean that naturally more flexible cells would be easier for parasites to invade, which raises some interesting questions.

– Marion Koch

The parasites have molecular motors that allow them to push their way into cells, and this was thought to be all that was required for invasion. However, now researchers led by a team at Imperial College London have found that the parasites also change the properties of red cells in a way that helps them achieve cell entry. The results are published in Proceedings of the National Academy of Sciences.

On binding to the surface of the red cell, the parasites cause the red cell membrane to become more bendy or pliable, making it easier for the driving parasite to push inside.

Differences in red blood cell stiffness, due to age or increased cholesterol content, could influence the parasite’s ability to invade. This suggests that red blood cells with higher cholesterol levels could remarkably be more resistant to invasion and therefore infection.

Investigating the host

Lead author of the study Marion Koch, from the Department of Life Sciences at Imperial, said: “We have discovered that red cell entry is not just down to the ability of the parasite itself, but that parasite-initiated changes to the red blood cells appear to contribute to the process of invasion.

“This could also mean that naturally more flexible cells would be easier for parasites to invade, which raises some interesting questions. Are parasites choosy about which cells to invade, picking the most deformable? Is susceptibility to malaria modified by fat or cholesterol content, or the age of circulating red blood cells?”

Lead researcher Dr Jake Baum, also from the Department of Life Sciences at Imperial, added: “This suggests we should be investigating not just parasite biology, but also how the body’s own red blood cells respond.

“There are therapies developed for diseases like HIV that strengthen the body’s responses in addition to tackling the ‘invader’. It’s not impossible to imagine something similar for malaria, for example looking at a host-directed drug target and not just the parasite.”

Measuring deformability

In order to bind to red blood cells, the parasite carries molecules that interlock with receptors on the cells’ surface. These molecules are similar to those used by the body’s own immune system to alter the cells’ properties, so the team wondered if they did the same thing for the parasite.

To find out, the team exposed red blood cells to parasite molecules and measured how much cells deformed as a result.

In one method, in collaboration with the University of Dresden, they filmed 1000 cells per second passing through a narrow channel. Using this approach, they were able to determine cell deformability by measuring how elongated the cells became during transit through the channel.

Next, the team collaborated with Dr Nicholas Brooks from the Department of Chemistry at Imperial to precisely measure where this deformation came from. They measured how much the cells deviate from their normally circular shape as their membranes naturally fluctuate or flicker.

The critical change appeared to be to the ‘bending modulus’ of the cells. The bending modulus is a measure of how much energy it takes to bend the cell membrane. The molecules tested reduced the bending modulus, meaning the parasite would require less energy to push its way in.

Malaria is a notoriously tricky infectious disease. Because of a unique genetic flexibility, it is able to change surface proteins, avoiding the immune response and greatly complicating vaccine development. Furthermore, the parasite is transmitted by mosquitoes, which are difficult to control. Insecticides work, but mosquitoes can develop resistance to them.

One method widely used to control malaria is for governments or charities to provide families with insecticide-treated bed nets. Overall, this strategy is very successful, and it has been credited with preventing some 451 million cases of malaria in the past 15 years. But bed nets are not successful everywhere. In some parts of the world, mosquitoes develop “behavioral resistance”; i.e., they learn to avoid bed nets by biting people earlier in the day.

A team led by Lisa Reimer of the Liverpool School of Tropical Medicine monitored mosquito behavior in villages in Papua New Guinea before (2008) and after (2009-2011) the distribution of bed nets. Data from one of the villages, Mauno, depicts a very noticeable shift in mosquito feeding behavior. (See graphs on the right.)

Before bed nets were distributed in 2008, the median biting time for mosquitoes was around midnight. After the distribution, the median time shifted back to 10 pm. Also, a greater proportion of mosquitoes took their dinner even earlier, from 7 to 9 pm.

Worryingly, it’s unclear whether the bed nets were effective at preventing malaria transmission. The number of bites per person per night dropped after the introduction of bed nets, but started to climb in subsequent years as mosquitoes began to adapt. Additionally, the prevalence of malaria infection in humans — arguably, the only statistic that actually matters — dropped in one village, remained the same in a second, and ticked up slightly (albeit insignificantly) in a third.

Despite the mixed results in Papua New Guinea, Dr Reimer believes that bed nets should continue to be used worldwide as part of a mosquito control strategy. However, she notes that behavioral resistance may prove just as vexing as insecticide resistance and, in some locations, may limit the efficacy of bed nets.

Thus, mosquitoes must be monitored for both behavioral and insecticide resistance, as the little creeps stubbornly refuse to die and may be cleverer than we thought.

Research team members check an attractive toxic sugar bait station on the outside wall of a home in Mali. In preliminary tests, the stations, which attract and kill malaria-carrying mosquitoes, caused populations of the bloodsuckers to plummet. (Westham Innovations)

Vaccines and genetic engineering grab the spotlight, but the Bill & Melinda Gates Foundation’s quiet funding for simple, new mosquito controls could be about to pay off in the effort to eradicate malaria.

Since Bill and Melinda Gates galvanized the global health world with their 2007 call to eradicate malaria, researchers have been scrambling for new tools to get the job done.

The lineup includes headline-grabbing marvels like genetically engineered mosquitoes, a laser fence to zap the malaria-carrying bugs and a silver-bullet vaccine. But there’s no telling when — or if — any of those technologies will actually pan out.

Meanwhile, a less flashy Bill & Melinda Gates Foundation initiative could be about to pay off with two potentially game-changing new ways to kill mosquitoes. Though simple and environmentally friendly, both approaches crashed mosquito populations in initial field trials in Africa.

Private companies already exist to commercialize the products, which could be deployed within a few years. And both also show promise for helping Americans battle mosquitoes in their own backyards.

“There’s lots of innovation, lots of cool ideas for malaria, but we really need things that can start saving lives in a timeline of three to five years,” said Penn State University entomologist Matt Thomas. “Simply having a great idea that sits on the lab bench isn’t going to do that.”

Humble insecticides have been the workhorse of every successful malaria elimination drive, including those that banished the disease from the United States and Europe. Since 2000, malaria deaths worldwide have fallen by half, and almost 80 percent of the gains are attributed to wider use of insecticide-treated bed nets and indoor spraying.

It’s cheaper and easier to develop new methods of mosquito control than to develop and gain approval for new drugs or vaccines, said Dan Strickman, a senior program officer at the Gates Foundation. But mosquitoes will eventually develop resistance to any conventional insecticide. Almost since its founding the Gates Foundation has been quietly investing in research on novel insecticides — while also searching for entirely new ways to control mosquitoes.

The two new technologies, which Strickman says could be “transformational,” capitalize on mosquito behavior. One turns an entire house into a toxic trap using humans as bait. The other lures mosquitoes with the scent of their primary food — which isn’t blood.

“These are tools that don’t just replace something that we do now,” Strickman said. “They do something different.”

The house trap was dreamed up under a mango tree in a Tanzanian village where Thomas, Dutch entomologist Bart Knols and colleagues gathered for a brainstorming session.

One of the topics was an odd preference on the part of malaria-carrying mosquitoes for slipping into houses via the gap between the walls and roof that’s common in many African dwellings. The scientists came up with the idea of inserting plastic tubes, called eave tubes, under the roofline and closing off the rest of the gap.

The mosquitoes, which bite indoors at night, are lured into the tubes by the scent of humans in the house. But instead of a tasty blood meal, the insects encounter a pesticide-coated mesh insert that douses them with poison.

With funding from the European Union, the researchers tested the concept by building an experimental village inside a screened enclosure the size of two tennis courts. They seeded a small marsh with malaria-free mosquitoes to establish a self-sustaining population and recruited volunteers to act as bait, sleeping in houses equipped with eave tubes and window screens.

The results were “incredible,” Strickman said. “The mosquitoes were basically gone, without spraying, without a lot of use of insecticides.”

The Gates Foundation was so impressed that the giant philanthropy bypassed its normal funding channels and anted up $10.2 million for large-scale tests that will include malaria monitoring.

The work will start early next year in 40 villages in the West African nation of Ivory Coast. Half the villages will get eave tubes, while the other half will use conventional mosquito control, Thomas explained.

Computer modeling suggests that installing eave tubes in even half the homes in some African communities could have a significant impact on malaria, he added. After the initial cost of installation, the only expense would be replacing the insecticide-coated inserts a couple of times a year.

A Dutch company, In2Care, is already manufacturing the tubes and is part of the research. “This is a tool that can be made field-ready,” Thomas said.

Workers drill holes along the roofline of a house in Kenya to install eave tubes to kill malaria-transmitting mosquitoes. In initial trials, mosquito populations in the village crashed. (Penn State University)

Eave tubes target mature female mosquitoes, which only feed on blood in order to produce eggs. The other new approach to mosquito-killing exploits the insects’ main food source — which is nectar.

Watching mosquitoes flit around flowers gave Israeli scientists the inspiration for using sugar to lure mosquitoes into a trap. The team got an early grant from the Gates Foundation, and was later funded by the U.S. military.

What emerged is the concept called attractive toxic sugar bait, or ATSB.

The idea is to use a bait that draws mosquitoes with its sweet scent, but is mixed with a small amount of insecticide. “As long as the mosquitoes come and feed on these things, they’re going to die,” Strickman said.

It took years of trial and error with solutions ranging from guava juice to fermented fruit brews for the scientists to develop a long-lasting, patented bait based on dates and sugar. A variety of insecticides can be used, including benign compounds like boric acid and garlic oil.

Tests in Israel and West Africa showed that use of toxic sugar bait, either as a spray or bait stations, can reduce mosquito populations by 90 percent or more. It seems to work well even in places with a lot of natural sugar sources, like flowers and rotting fruit.

The approach is especially powerful because it can kill males and young females, Strickman said. But early versions also killed bees and other pollinators. The newest bait stations, which encapsulate the lure and insecticide in a flat, black membrane, don’t seem to attract beneficial insects, but more research is needed, said University of Miami environmental health expert John Beier, a member of the project science team.

The Israeli-based manufacturer Westham Co. is a key player in the trials and is already thinking about how to gear up for commercial production, Strickman said. Equipping a house with two long-lasting bait stations could cost as little as $5 and could be enough to control local mosquito populations, he added.

“We hope to have a product in Africa on the market as early as 2019,” Strickman said.

Research on eave tubes and toxic sugar baits has already generated products for mosquito control in the U.S. and other developed countries.

Researchers tested the effectiveness of attractive toxic sugar bait stations on mosquitoes released inside screened enclosures in the West African nation of Mali. (Westham Innovations)

Americans can buy a sugar-based spray from Terminex that kills mosquitoes with garlic oil, or hire the company to have their property sprayed. Backyard bait stations aren’t available yet but eventually will be, Beier said.

“I would certainly buy one at Home Depot if I could,” he said.

In2Care, the company that makes eave tubes, also produces stand-alone mosquito traps that use the same type of insecticide-coated mesh to deliver the fatal dose. The traps were recently approved for emergency use in the U.S. against the mosquitoes that transmit Zika, dengue and other viruses.

Funding from Gates and others has created a golden age in what’s called vector control — the unglamorous slog of battling mosquitoes, said Karl Malamud-Roam, manager of Rutgers University’s public health pesticides program.

“There hasn’t been any time in the last hundred years when so many new … ideas have been floating around, with people who care and money to test things,” he said.

For malaria, the next challenge will be to figure out what mix of mosquito killers will work best in combination with existing medical treatments to beat back the disease and shrink its footprint over the next 10 to 15 years, he said.

By that time, some of the futuristic techniques like genetic engineering or a better vaccine might be ready for prime time, said Thomas, of Penn State.

“Hopefully, at that point they will be just mopping up.”

Some of the reporting for this story was conducted during a fellowship sponsored by Malaria No More, which is partly funded by the Bill & Melinda Gates Foundation.

The superbugs – malaria parasites that can beat off the best current treatments, artemisinin and piperaquine – have spread throughout Cambodia, with even fitter multidrug resistant parasites spreading in southern Laos and northeastern Thailand.

“We are losing a dangerous race to eliminate artemisinin resistant…malaria before widespread resistance to the partner antimalarials makes that impossible,” said Nicholas White, a professor at Oxford University in Britain and Mahidol University in Thailand who co-led the research.

“The consequences of resistance spreading further into India and Africa could be grave if drug resistance is not tackled from a global public health emergency perspective.”

More than half the world’s people are at risk of malaria infection. Most victims are children under five living in the poorest parts of sub-Saharan Africa.

Recent progress against the mosquito-borne disease has been dramatic and numbers falling ill have been significantly reduced, but it still kills more than 420,000 people each year, the World Health Organization says.

Malaria specialists worldwide say emerging drug resistance in Asia is now one of the most serious threats to that progress.

From the late 1950s to the 1970s, chloroquine-resistant malaria parasites spread across Asia and then into Africa, leading to a resurgence of malaria cases and millions of deaths.

Chloroquine was replaced by sulphadoxine-pyrimethamine (SP), but resistance to SP subsequently emerged in western Cambodia and again spread to Africa.

The fear now is that the same pattern of resistance spread and the resurgence will repeat itself.

“We now see this very successful resistant parasite lineage emerging, outcompeting its peers, and spreading over a wide area,” said Arjen Dondorp, of the Mahidol Oxford Tropical Medicine Research Unit in Thailand, who co-led the work.

Efforts to control malaria in Asia must be stepped up urgently “before it becomes close to untreatable”.

In their study in the Lancet Infectious Diseases journal, the scientists said that after examining blood samples from malaria patients in Cambodia, Laos, Thailand and Myanmar, they found that a single mutant parasite lineage, known as PfKelch13 C580Y, has spread across three countries, replacing parasites containing other, less artemisinin-resistant mutations.

They explained that while the C580Y mutation does not necessarily make the parasite more drug-resistant, it does have other qualities that make it more risky – notably it appears to be fitter, more transmissible and able to spreading more widely.

For the first time, researchers have shown that the number of parasites each mosquito carries influences the chance of successful malaria infection.

The finding has implications for vaccine development and studies into how the disease spreads in the field.

The findings, from scientists at Imperial College London, may also explain why the only registered malaria vaccine, RTS,S, has had only partial efficacy in recent trials. Malaria is spread when mosquitoes bite humans and release microscopic parasites, which live in the salivary glands of the mosquitoes, into the person’s bloodstream.

These findings could have significant implications for public health. We have shown that the concept of relying on the number of bites alone to predict malarial burden is flawed.

– Dr Andrew Blagborough

The parasites then travel to the liver, where they mature and multiply for 8-30 days before spreading throughout the bloodstream and causing the symptoms of malaria.

Not every infectious mosquito bite will result in malaria. To determine the intensity of malaria transmission, researchers and international organisations like the World Health Organisation currently rely on a measure called the entomological inoculation rate (EIR): the average number of potentially infectious mosquito bites per person per year.

However, this does not take into account how infectious each of those bites may be – each bite is considered equally infectious. Previous studies using needle-injected parasites have suggested this may not be the case, but there have been no comprehensive studies using biting mosquitoes, which more accurately reflect real-world scenarios.

Now, in a study funded by the PATH Malaria Vaccine Initiative and the Medical Research Council, published in the journal PLoS Pathogens, researchers have determined that the number of parasites each individual mosquito carries influences whether a person will develop malaria. Some mosquitoes can be ‘hyperinfected’, making them particularly likely to pass on the disease.

Significant implications

In studies in mice, the researchers determined that the more parasites present in a mosquito’s salivary glands, the more likely it was to be infectious, and also the faster any infection would develop.

Study co-author Dr Andrew Blagborough, from the Department of Life Sciences at Imperial, said: “These findings could have significant implications for public health. We have shown that the concept of relying on the number of bites alone to predict malarial burden is flawed, and has probably hampered the successful use of control measures and the development of effective vaccines.

“It is surprising that the relationship between parasite density and infectiousness has not been properly investigated before, but the studies are quite complex to carry out.”

The team set up repeated cycles of infection, so that groups of infected mosquitoes containing variable numbers of parasites repeatedly bit sedated mice, transmitting malaria to them under a range of transmission settings.

This allowed them to track how many individual parasites different mosquitoes harboured, how many mice were infected as a result of exposure to them, and how long it took the mice to develop malaria.

Vaccine development

By conducting further studies with mice and human volunteers, the team were also able to explain why the malaria vaccine RTS,S is effective only around 50 percent of the time, and why any protection rapidly drops off after three years.

Vaccine development has come a long way, and this new insight should help future vaccine studies to be tested more rigorously.

– Dr Thomas Churcher

The vaccine was less effective when mice or humans were bitten by mosquitoes carrying a greater number of parasites. The researchers think this is because the vaccine can only kill a certain proportion of the parasites, and is overwhelmed when the parasite population is too large.

All malaria-affected regions will have a mix of mosquitoes carrying different parasite amounts. Dr Blagborough said: “The majority of mosquitoes in the wild are either uninfected or infected at quite low levels, but some individual mosquitoes are regularly very highly infected.

“As the levels of malaria drop in an area due to the successful use of interventions, the number of these hyperinfected mosquitoes is expected to drop – but they’re not totally prevented unless the intervention is very powerful.”

Study co-author Dr Thomas Churcher, from the MRC Centre for Outbreak Analysis and Modelling at Imperial, said: “Vaccine development has come a long way, and this new insight should help future vaccine studies to be tested more rigorously.

“However, in the end, it is unlikely that one magic bullet will eradicate malaria, and we should continue to seek and apply combinations of strategies for reducing the burden of this disease.”

Dr Morvern Roberts, programme manager for global infections at the Medical Research Council who funded the research, said: “Researchers have long wondered whether the more malaria parasites in a mosquito’s mouthparts, the more likely they are to infect a host with the disease. No one has been able to demonstrate this until now but the authors of this paper have shown that this is the case in both mouse models and in humans.

“As they suggest, this knowledge is extremely important to take into account when trying to develop vaccines for malaria and other vector-borne diseases.”

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